Abstract
We have previously reported that bovine papillomavirus type 1 (BPV-1) DNA can replicate its genome and produce infectious virus-like particles in short term virion-infected S. cerevisiae (budding yeast) cultures (Zhao and Frazer 2002, Journal of Virology, 76:3359–64 and 76:12265–73). Here, we report the episomal replications of BPV-1 DNA in long term virion-infected S. cerevisiae culture up to 108 days. Episomal replications of the BPV-1 DNA could be divided into three patterns at three stages, early active replication (day 3–16), middle weak replication (day 23–34/45) and late stable replication (day 45–82). Two-dimensional gel electrophoresis analysis and Southern blot hybridization have revealed further that multiple replication intermediates of BPV-1 DNA including linear form, stranded DNA, monomers and higher oligomers were detected in the virion-infected yeast cells over the time course. Higher oligomers shown as covalently closed circular DNAs (cccDNAs) are the most important replication intermediates that serve as the main nuclear transcription template for producing all viral RNAs in the viral life cycle. In this study, the cccDNAs were generated at the early active replication stage with the highest frequencies and then at late stable replication, but they appeared to be suppressed at the middle weak replication. Our data provided a novel insight that BPV-1 genomic DNA could replicate episomally for the long period and produce the key replication intermediates cccDNAs in S. cerevisiae system.
Highlights
Papillomaviruses (PVs) are a family of small doublestranded circular DNA viruses with more than 200 genotypes (Doorbar 2016)
We have previously reported that bovine papillomavirus type 1 (BPV-1) DNA can replicate its genome and produce infectious virus-like particles in short term virion-infected S. cerevisiae cultures (Zhao and Frazer 2002, Journal of Virology, 76:3359–64 and 76:12265–73)
We previously demonstrated that BPV-1 DNA could be detected in a small volume (2 mL) of S. cerevisiae cells infected with BPV-1virions at day 55 and 75 post-infection by 1% one-dimensional agarose gel electrophoresis (1-DAGE) and Southern blot hybridization of Hirt DNA (Zhao and Frazer 2002a, b)
Summary
Papillomaviruses (PVs) are a family of small doublestranded circular DNA viruses with more than 200 genotypes (Doorbar 2016). Human papillomaviruses (HPVs) have been demonstrated to be responsible for causing several human cancers and genital warts (Moody and Laimins, 2010). The persistent infection of high-risk human papillomavirus (hr-HPV) is closely related to the pathogenesis of cervical cancer and many other cancers. HPVs account for more than 30% of all infectionassociated cancers in humans (zur Hausen 2009). Preventive vaccines including 2-valent, 4-valent and 9-valent vaccines against HPV-associated cervical cancer are available, which prevent an estimated 92% of the cancers attributable to HPV types (Frazer and Levin 2011; Huh et al 2017; Zhang et al 2020a). Considering that the preventive vaccines are unable to wipe out the existing
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